204589-82-2

Usage

Uses

Used in Pharmaceutical Industry:
(3R,4S)-1-(4-Fluorophenyl)-2-oxo-4-[4-(benzyloxy)phenyl]-3-azetidinepropanoic acid is used as a key reagent for the synthesis of antihypercholesterolemia drug Ezetimibe. This application is due to its ability to contribute to the development of a medication that helps lower cholesterol levels in the body, thus reducing the risk of cardiovascular diseases.
Additionally, (3R,4S)-1-(4-Fluorophenyl)-2-oxo-4-[4-(benzyloxy)phenyl]-3-azetidinepropanoic acid is used as a reagent for the preparation of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235), which is designed as an inhibitor of cholesterol absorption. This application highlights its importance in the development of drugs that can effectively manage cholesterol levels and contribute to overall heart health.

InChI:InChI=1/C25H22FNO4/c26-19-8-10-20(11-9-19)27-24(22(25(27)30)14-15-23(28)29)18-6-12-21(13-7-18)31-16-17-4-2-1-3-5-17/h1-13,22,24H,14-16H2,(H,28,29)/t22-,24-/m1/s1

Upstream product

• 204589-80-0 methyl 3-((2S,3R)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl)propanoate 
• 219653-96-0 (Z)-1-(4-(benzyloxy)phenyl)-N-(4-fluorophenyl)methaneimine 
• 1412967-14-6 (3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-hydroxypropyl)azetidin-2-one 
• 1046809-85-1 3-[(2S,3R)-2-(4-benzyloxy-phenyl)-1-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester 

Downstream Products

• 190595-65-4 (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one 
• 204589-80-0 methyl 3-((2S,3R)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl)propanoate 
• 1412967-14-6 (3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-hydroxypropyl)azetidin-2-one 
• 934245-14-4 3-[(2S,3R)-2-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]-N-methoxy-N-methylpropaneamide 

Relevant academic research and scientific papers

Synthesis and Evaluation of 2-Azetidinone and 1H-Pyrrole-2,5-dione Derivatives as Cholesterol Absorption Inhibitors for Reducing Inflammation Response and Oxidative Stress

Excess lipid accumulation can initiate the development and progression of atherosclerotic lesions, thus eventually leading to cardiovascular disease. Lipid-lowering medication therapy is one of the cornerstones of cardiovascular disease therapy. On the basis of the cholesterol absorption inhibitor ezetimibe, we successfully synthesized seven 2-azetidinone derivatives and eighteen 1H-pyrrole-2,5-dione derivatives. Most of the new compounds significantly inhibited cholesterol uptake in vitro. In addition, one of the most active inhibitors, 3-(4-fluorophenyl)-1-[(3S)-3-hydroxy-3-(4-hydroxyphenyl)propyl]-4-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione (14q), showed no cytotoxicity in L02 and HEK293T cell lines. Further evaluation indicated that 14q inhibited considerably the amount of TNF-α, ROS, MDA, and LDH in vitro. Therefore, 14q might be a novel cholesterol absorption inhibitor.

Formal Synthesis of Ezetimibe Using a Proline-mediated, Asymmetric, Three-component Mannich Reaction

The formal total synthesis of ezetimibe was accomplished using a proline-mediated, asymmetric, three-component Mannich reaction as the key step. The two stereogenic centers on the β-lactam skeleton of ezetimibe were controlled by the syn-selective asymmetric Mannich reaction, followed by isomerization.

An improved and scalable process for the synthesis of ezetimibe: An antihypercholesterolemia drug

An efficient, cost-effective and large-scale synthesis of ezetimibe 1, an antihypercholesterolemia drug, is described. Chiral oxazolidinone chemistry was used to fix the required stereochemistry of the β-lactam ring, and the chiral oxazaborolidine chemistry was used to fix the hydroxyl group stereochemistry. The synthesis significantly lowers the cost and provides easy access to ezetimibe on large scale.

Process for the preparation of ezetimibe and derivatives thereof

The present invention relates to the method of preparing of ezetimibe and in particular to novel intermediates for its synthesis and an improved process for preparing such intermediates. Said intermediates may be obtained in high yields and purity in a fast and cost efficient manner. The present invention relates to a novel crystalline form of ezetimibe as well.

IMPROVED PROCESS FOR THE PREPARATION OF EZETIMIBE AND ITS INTERMEDIATES

The present invention provides an improved process for the preparation of ezetimibe through novel organic amine salt compounds of general formula (1). The present invention also relates to a highly pure ezetimibe and 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl) azetidin-3-yl)propionic acid compound.

PROCESS FOR PREPARING HIGHLY PURE EZETIMIBE USING NOVEL INTERMEDIATES

The present invention relates to an industrially advantageous process for the preparation of ezetimibe of formula (I) in high yields by using novel benzyl ester intermediates. The present invention further provides a process for the purification of ezetimibe of formula (I).

PREPARATION OF EZETIMIBE

A process for preparing ezetimibe.

IMPROVED PROCESS FOR THE PREPARATION OF EZETIMIBE

The present invention relates to a cost effective and industrially advantageous process for the preparation of (3R,4S)-l-(4-Fluorophenyl)-3-[3(S)-3-(4-fluorophenyl)-3 - hydroxypropyl)]-4-(4-hydroxyρhenyl)-2-azetidinone, referred to here as Ezetimibe, it is represented as formula (1).

Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions

The present invention provides compositions, therapeutic combinations and methods including: (a) at least one lipid modulating agent; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity and lowering plasma levels of sterols or 5α-stanols.

Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)- hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption

(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]- (4S)-(4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.